DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR MEASURING DISSOLUTION RATE OF THE ENTIRE DOSE IN BIORELEVANT MEDIA

Transcription

1 DISSOLUTION RATE LIMITING AUC: SIMPLE METHODOLOGY FOR MEASURING DISSOLUTION RATE OF THE ENTIRE DOSE IN BIORELEVANT MEDIA Jesse Kuiper and Paul Harmon

2 Outline 2 Understanding the path to absorption (and the meaning of dissolution rate controlled absorption) Understanding the dissolution contribution of the entire dose 1X Biorelevant Dissolution Application of 1X Biorelevant Dissolution concept An in-depth case study Conclusions

3 Outline 3 Understanding the path to absorption (and the meaning of dissolution rate controlled absorption) Understanding the dissolution contribution of the entire dose 1X Biorelevant Dissolution Application of 1X Biorelevant Dissolution concept An in-depth case study Conclusions

4 4 Formulation-Based Absorption: Any Solid Oral Dosage Form (The MiMBA View ) tablet granules API Particles (10-50 um) Dissolved Drug molecules lumen GI Tract flux drug absorbed = A membrane * [drug lumen ] * K permeability Dissolution Rate (of API Particle) ~ (Particle SA)*(Diffusion Term)*(C s C l ) Concentration difference term (C s C l ) drives dissolution rate. If drug has high solubility dissolution rates are fast given fixed particle size. If drug has low solubility, disso rate is slow particles may come out of pipe at end 4

5 Dissolution Rate Limited AUC 5 lumen API Particles 1 Dissolved Drug molecules 2 If 1 > 2, then dissolved drug concentration in the GI is pegged at the solubility limit this is solubility/permeability limited exposure. In this regime, different formulations of same API give similar AUC. If 2 > 1, then dissolved drug concentration in GI is below the drug solubility limit, this is dissolution rate limited (disso rate can t keep up with permeability loses). In this regime AUC may be sensitive to formulation details...(api PSD, for example) How to measure/compare aggregate API particle dissolution rates as they dissolve in aggregate (from different formulations) as this dissolution drives the [API] in GI fluids to the its solubility limit?

6 How to Measure Aggregate Flux Whole Dose Must Dissolve 6 API Particles In the case where C provides constant sink for dissolved drug to go, the rate 1 of transition from A to B matters, regardless of amount dosed, therefore the dissolution behavior of the entire dose matters lumen 1 Dissolved Drug molecules 2 sink How can this be measured? Mimic the system! Put the dose inside a permeable membrane (only drug in solution gets through) and have large volume on other side of membrane to keep [drug] below its solubility limit or some sort of way to remove drug outside membrane (inside always driving to sol limit). Also, biphasic dissolution (aqueous/organic) Is there a more elegant way? Simply put a portion of dose into BR media AT the solubility limit, compare disso profile (rate) to get there! THIS IS 1X BIORELEVANT DISSOLUITION

7 Outline 7 Understanding the path to absorption (and the meaning of dissolution rate controlled absorption) Understanding the dissolution contribution of the entire dose 1X Biorelevant Dissolution Application of 1X Biorelevant Dissolution concept An in-depth case study Conclusions

8 Understanding 1X Dissolution in Terms of Single Particle Dissolution 8 = 3 Description of the dissolution of a single particle at infinite dilution Concentration Single Particle Prediction vs 1x Dissolution Single Particle Prediction Solubility Limit 1x Disso For a given population of homogeneous particle size, 1x sink Dissolution will initially match the single particle dissolution rate predicted by the above equation, but as the C S term approaches the solubility limit C S (C S -C LIM ), therefore the rate slows Amidon, Lenneräs, Shah and Crinson, Pharm. Res. Vol. 12, No. 3, 1995

9 9 dm dt Particle (of API) Dissolution Modeling Dissolution Rates at 1X Solubility API particle D = A( C s Cb) δ C s m = mass t = time D = diffusion coefficient δ = diff. layer thickness (fn. size) diffusion layer δ bulk solution C b Model based on drug particle and the external mass transfer out from the unstirred water later (Nernst-Brunner or Noyes-Whitney) Assumes solubility limit is quickly reached in a thin layer around particle then drug molecule diffusion out of the unstirred layer into the bulk soln is the mass transfer rate limiting step. need accurate PSD*, solubility value, and diffusion coefficient of molecule. smaller PSD means more surface area per mass, smaller diffusion layer thickness so dissolution rate goes up! *PSD under dissolution conditions.. A = surface area C s = conc in stagnant layer C b = conc in bulk solution

10 Theoretical Example: Working at 5 μg/ml Solubility Limit (Calculated) mg in 500 ml API particle size 1) This is why smaller API size is better IF disso rate limited! 2) What would happen if this was done at dose relevant concentration? SA/V ratio = 1/r

11 Dissolution at Dose Relevant Concentrations 11 API particle size Example - If dose is 100 mg, in 500 ml Fassif = 200 ug/ml = 40X sol. limit (C S -C LIM ) approaches 0 rapidly The dissolution experiment loses resolution (cannot differentiate between particle sizes)

12 Practically, What Working at 1X Means 12 Using the 5 μg/ml solubility in FaSSIF example, and the 100 mg dose That s a lot of FaSSIF! To work at 1X with a complete 100 mg tablet then would require a 20,000 ml volume We work with granules (example here, 1/40 th weight of a tablet in 500 ml fassif) or portions of tablets or pre-disintegrated in SGF

13 1X Dissolution is Readily Modeled 13 If API is dispersed properly and that PSD put into the disso calculation calc/experiment agree well why slower rate at end? APIs pre-dispersed prior to putting in FaSSIF - drug added at 1 mg/ml

14 This Approach Allows Quantitative Comparisons Across Formulation Types 14 Formulation Attribute Formulation processes strive to disperse the API particles to their primary size from a tablet Granulation of API Addition of Surfactants 1x Dissolution Response Formulations that do this better will have faster rates of dissolution than those that do this poorly Granulation can help with dispersion of particles in dissolution also over granulation can add additional dissolution rate slowing (increase in ρ term (particle density) Helping wet the particles may improve dissolution rate Understanding the dissolution rate of well dispersed API particles is the first step in evaluating dissolution performance as a very well dispersed formulation with very fast granule dissolution will approach dispersed API dissolution rate.

15 Representative 1X Data Comparing Formulation Components 15 API calculated dispersed API optimize WG granule with surfactant RC granule Tablet

16 Outline 16 Understanding the path to absorption (and the meaning of dissolution rate controlled absorption) Understanding the dissolution contribution of the entire dose 1X Biorelevant Dissolution Application of 1X Biorelevant Dissolution concept An in-depth case study Conclusions

17 Introduction of the Dosage Form 17 2x FaSSIF, ph Adjusted SGF FaSSIF 2-Stage Dissolution First stage preps the dose form (like the stomach), portion to the second stage

18 Example BC Study Low Solubility API, all Formulations Amorphous SD 18 Drug is BCS Class II (poorly soluble, readily absorbed) Formulation 1 (reference formulation): VA-64 / Drug C / SLS (65 : 30 : 5) in amorphous SD dispersion intermediate (SDI) Formulation 2: Removed SLS from dispersion. Potential issues with crystallization of SLS out of dispersion observed in Formulation 1 stability studies. Is it really needed IN the dispersion? Add same SLS to tablet external to SDI. Formulation 3: Removed VA-64 and SLS; just SD amorphous drug A in the SDI. Combination products need more tablet volume is the VA-64 polymer in the dispersion really needed? Add SLS externally to tablet. At this time, 1X biorelevant dissolution was not a common practice

19 Formulations Appear Equivalent by Typical Biorelevant Dissolution Methodology and Animal pk Studies 19 Drug C Apparent amorphous solubility Drug C Formulation 1 vs Formulation 3 at Dose Relevant Concentration - 2 Stage Biorelevant dissolution SGF FaSSIF Biorelevant dissolution at dose relevant concentration informed animal study ug/ml (post 80K) [TARGET] in FaSSIF is 1200 μg/ml Formulation 3 Formulation Formulation 1 and Formulation 3 bracket expected range of dissolution behavior time (min) Clinical Dosage Forms at that time...thought all 3 amorphous formulations would be similar..

20 Example 2 Human AUC BC Study #1 (high dose) 20 Formulation 1 ~10X difference in C MAX Formulation 2 Something is happening with these enabled formulations beyond solubility enhancement! Recall the Formulation 1 system VA-64, SLS, API Formulation 3 Formulation 4

21 21 Revisit Formulation How Does it Behave in solution? Speciation: formulations gives different populations of Sub 1μm Particles after SGF stage. What happens to the SDI particles upon exit of the VA-64? fraction of dose sub - 1 micron Formulation 1 80% Formulations are dissolved in SGF at dose relevant Concentrations (2.4 mg/ml) Formulation 2 20% Formulation 3 < 5% End of SGF stage: huge particle size differences! 80% of Formulation 1 is sub - 1 micron; 20% for formulation 2, and formulation 3 is just the 40 um mean PSD

22 Formulation 1 Gives Large Population of Sub 1μm Particles (in-situ Particle Size Reduction) 22 Volume (%) Particle Size Distribution 20% of formulation 1 PSD ~10um Formulation 3 mean PSD ~40 um 80% of Formulation 2 mean PSD ~20 um Particle Size (µm) micron particles by Malvern Mastersizer, looking at SDI s alone post SGF stage at 2.4 mg/ml Drug A level Formulation1 not only forms larger amount of sub-micron particles, but its micron range particles are smaller than those measured for formulations 2 and 3 post SGF

23 So how do we do Biorelevant Dissolution in this case? 23 Entire dose influences dissolution at dose relevant concentrations, dissolution captures ~5% of dose in solution Recall, for these formulations, the amorphous dispersion is VA64 The polymer readily dissolves in the stomach (SGF), the speciation event will happen prior to the region where absorption can occur So, you do 1 st stage of dissolution at dose relevant concentration (dose/250 ml SGF), then, DILUTE a portion of sample into FaSSIF at the solubility limit of the drug ( 1X ) and measure the relative dissolution rates -dilution could be 2-200X depending on amorphous drug solubility

24 1x Sink Biorelevant Dissolution Clearly Differentiates Formulations Drug C Formulations 1-3: 1x Sink dissolution vs Simulated Now formulations look very different! Formulation 1 very rapid rate to sol. limit 30 ug/ml Formulation 3 very slow rate to sol. limit Time (min) Formulation 1 - Measured Formulation 2 - Measured Formulation 3 - Measured 24

25 Dissolution Rates Readily Modeled 25 SDI Below 1 μm Above 1 μm 50 Simulated Dissolution Curves - Based Upon Measured PSD Formulation 1 (30% Drug C, 64.25% VA- 64, 5% SLS, 0.75% AO) Formulation 2 (33% Drug C, 65.5% VA-64, 0.5% AO) Formulation 3 (99.5% Drug C 0.5% AO) 80% of particles nm 20% of particles nm 20% of particles ~10 μm (vol. mean) 80% of particles ~20 μm (vol. mean) 0% 100% ~40 μm (vol. mean) ug/ml dissolved Formulation 1 10 Formulation 2 Formulation time (min) Particle size distributions for previous slide used in simulated dissolution

26 Comparison - Data vs Simulations 26 Drug C Formulations 1-3: 1x Sink dissolution vs Simulated In-situ particle size dominates dissolution behavior for dispersions of Drug C ug/ml Formulation 1 - Measured Formulation 2 - Measured Formulation 3 - Measured Formulation 1 - Simulated Formulation 2 - Simulated Formulation 3 - Simulated Time (min) Dissolution rate is an indicator of pk performance

27 Outline 27 Understanding the path to absorption (and the meaning of dissolution rate controlled absorption) Understanding the dissolution contribution of the entire dose 1X Biorelevant Dissolution Application of 1X Biorelevant Dissolution concept An in-depth case study Conclusions

28 Summary and Conclusions 28 When dissolution rate is the rate limiting step in absorption, it is important to understand the effective dissolution rate of the entire dose 1X Biorelevant Dissolution is a discriminating dissolution method that allows for evaluation of subtle formulation changes 1X Biorelevant Dissolution is a simple yet powerful tool to predict exposure in animal and human subjects

29 Acknowledgements 29 Paul Harmon Wei Xu Michael Socki Adam Socia Kendra Galipeau Melanie Marota Justin Moser Leah Buhler Allen Templeton Mark Mowery